ABSTRACT The Mayo Clinic Study of Aging (MCSA) has been functioning as a population-based study of cognition and aging since 2004. Over that timeframe, we have evaluated longitudinal cognitive trajectories of individuals who are cognitively normal, have mild cognitive impairment (MCI) and dementia. We have evaluated epidemiologic features of MCI and in recent years have evaluated many of the biomarkers of aging and Alzheimer's disease (AD) including MRI, FDG PET, amyloid PET and tau PET. In the current application, we will evaluate the recently published National Institute on Aging-Alzheimer's Association AD Research Framework using our population-based cohort. In Aim 1, we will predict and assess the role of risk factors of cognitive decline using the Framework's syndromic clinical classification of cognitively unimpaired, MCI and dementia participants. In Aim 2, we will predict cognitive decline in the Framework according to the newly proposed numeric staging scheme for randomized controlled trials among amyloid positive persons. In addition, since we are evaluating a representative sample of the entire community, we will also evaluate the numerical staging scheme in amyloid negative persons as well as in the entire population. Since it is recognized that cerebrovascular disease plays an important role in aging, in Aim 3 we will evaluate the impact of cerebrovascular disease in aging and cognition as well as its interactions with AD pathology. We will also develop novel MRI cerebrovascular disease measures using advanced methods. Biomarker measures of AD are often expensive and/or invasive, and, as such, are not practical from a public health perspective, and, therefore, in Aim 4, we will determine and compare the utility of plasma amyloid-beta, p-tau181, total tau and neurofilament light (NfL) as noninvasive biomarkers of cognitive decline and assess interactions with imaging biomarkers of amyloid, tau, neurodegeneration and vascular disease. Finally, since sharing the rich resources of the MCSA are important, in Aim 5, we outline our proposed mechanisms for data sharing that include review of proposals, standardized data sharing agreements and logistics for sharing the data. We are hopeful that the continuation of the MCSA will provide valuable information for the field of aging and AD.